# Early Events in Protein Folding

> **NIH NIH R01** · EMORY UNIVERSITY · 2021 · $356,443

## Abstract

Project Summary/Abstract
 The structure-function paradigm is a powerful guiding principle that underlies much of our understanding
of biological processes. What is often neglected in this picture, however, is the flexibility of protein structures.
This flexibility is necessary for a protein to fold to its native, active structure. Furthermore, protein function
requires evolution of this native structure with time. Therefore, the dynamics of the protein structure and
associated solvent water provide the critical connection between structure and function. The overall goal of
this proposal is to elucidate the functional dynamics of hemagglutinin and M2 proton channel that enable
influenza virus infection, a problem with significant public health implications. The mechanisms explored in
this work are also relevant to other enveloped viruses, in particular HIV. More generally, membrane fusion
and proton transport through proteins are of high fundamental interest and we expect the insight gained in
these specific studies will contribute to the understanding of a broad range of related systems. We plan to
pursue three specific aims:
 1) Determine the mechanism of hemagglutinin mediated membrane fusion. We will test a new model for
protein mediated membrane fusion that is based on molecular dynamics simulations of this process. We have
developed unique methodology base on a laser induced pH jump to initiate the fusion process, and structure
specific spectroscopic methods to characterize the hemagglutinin refolding dynamics that drive membrane
fusion. This viral protein serves as an archetype for understanding the general mechanism of membrane
fusion as a ubiquitous membrane transport process.
 2) Determine the mechanism of fusion pore formation. We will test the hypothesis that the hemagglutinin
trans-membrane domain (TMD) and fusion peptide (FP) form an oligomeric complex that opens and stabilizes
the fusion pore.
 3) Determine the molecular mechanism of actively gated proton transport. This work will on a focus on
the influenza M2 proton channel, an important model ion channel. Understanding transport of protons through
protein channels is critical to many essential biological processes as well as replication of the influenza virus.
 These aims are linked intellectually by energy landscape concepts and operationally by the methodology
developed in our lab for studying both protein and membrane dynamics. Our unique approach will allow us to
identify specific protein motions involved in protein mediated membrane fusion and proton channel activation.
We expect this work to provide important new insight into the factors that shape the energy landscape of
membrane proteins and the coupled membrane dynamics.

## Key facts

- **NIH application ID:** 10217148
- **Project number:** 5R01GM053640-24
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** RICHARD BRIAN DYER
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $356,443
- **Award type:** 5
- **Project period:** 1996-06-01 → 2023-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10217148

## Citation

> US National Institutes of Health, RePORTER application 10217148, Early Events in Protein Folding (5R01GM053640-24). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10217148. Licensed CC0.

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